The advent of highly active antiretroviral therapy (ART)

treatment complications in HIV Long-Term Treatment Complications in HIV Disease Case Studies and Commentary, Elisa I. Choi, MD, and Howard Libman, MD cme jointly sponsored by Wayne State University School of Medicine and JCOM The following article, Long-Term Treatment Complications in HIV Disease is a continuing medical education (CME) article. To earn credit, read the article and complete the CME evaluation on pages 355 and 356. Program Audience Physicians caring for patients with HIV disease. Educational Needs Addressed Highly active antiretroviral therapy (ART) has resulted in dramatic declines in morbidity and mortality among patients infected with HIV. However, a number of complications are associated with long-term ART, including lipodystrophy syndrome, lactic acidosis/acidemia, peripheral neuropathy, and bone disorders. These complications can have a significant negative impact on the quality of life of HIV-infected patients and may predispose to further comorbidities, such as atherosclerotic disease and premature bone fractures. It is important that clinicians caring for HIV-infected patients be aware of the adverse effects of treatment and management options. In this review, the clinical manifestations, risk factors, and pathophysiology of ART-related toxicity syndromes are explored, with an emphasis on clinical assessment and management. Educational Objectives After participating in this CME activity, physicians should be able to 1. Describe the clinical manifestations and pathogenesis of ART-related complications 2. Discuss the association of ART and risk for cardiovascular disease 3. Describe appropriate screening maneuvers for ART-related complications 4. Understand management approaches for ARTrelated complications The advent of highly active antiretroviral therapy (ART) in 1996 revolutionized the care of HIV-infected patients. Morbidity and mortality from opportunistic infections and malignancies have been greatly reduced, and HIV disease is now managed as a chronic medical condition. However, despite these benefits, longitudinal data from cohorts of HIV-infected persons have shown that long-term ART use is associated with several complications, including lipodystrophy syndrome, lactic acidosis/acidemia, peripheral neuropathy, and bone disorders (Table). These complications have had a significant negative impact on quality of life for many patients and may predispose to further comorbidities, such as atherosclerotic disease and premature bone fractures. In this article, we provide case examples of each of the major categories of ART-related complications and discuss their diagnosis and management. Case Study 1 Initial Presentation An asymptomatic 38-year-old man diagnosed with HIV infection 6 years ago presents for a routine visit. History At the time of diagnosis, the patient s baseline CD4 cell count was 140/mm 3 and his viral load was 82,600 copies/ ml. Other laboratory results included a fasting glucose of 84 mg/dl and a total cholesterol of 220 mg/dl, with a lowdensity lipoprotein (LDL) component of 140 mg/dl and a triglyceride level of 424 mg/dl. He was started on stavudine (d4t), lamivudine (3TC), and nelfinavir. His CD4 cell count increased to 460/mm 3 and his viral load has been less than 50 copies/ml. However, over the past year, he has become concerned about sunken cheeks. The patient has hypertension, but there is no history of diabetes mellitus, liver disease, or thyroid disease. He does not exercise regularly. There is a history of coronary artery disease in both parents and an older brother. He has From the Division of Infectious Diseases (Dr. Choi) and the Division of General Medicine and Primary Care (Dr. Libman), Beth Israel Deaconess Medical Center, Boston, MA. 342 JCOM June 2006 Vol. 13, No. 6 www.turner-white.com

case-based review Table. Complications Associated with Long-Term Antiretroviral Therapy (ART): Summary Points Lipodystrophy syndrome Common and multifactorial in etiology Characterized by body fat redistribution, dyslipidemia, and/ or glucose intolerance/diabetes mellitus Lack of standardized case definition has made interpretation of literature problematic Optimal management remains unknown Hormone therapy, cosmetic surgery, and local injection therapy may be useful in the management of body morphology changes Statins, fibrates, fish oil, and/or insulin-sensitizing agents may be useful in the management of the metabolic abnormalities Modification of ART regimen may be beneficial in some instances There are conflicting data about risk of atherosclerotic disease Lactic acidemia/lactic acidosis Asymptomatic lactic acidemia is common in patients on NRTIs, but symptomatic acidemia and acidosis are not Related to mitochondrial toxicity from interference with DNA-polymerase Clinical manifestations are variable and nonspecific Management consists of stopping NRTI in symptomatic patients with high lactate levels Screening for this condition in the absence of symptoms is unlikely to be helpful Peripheral neuropathy HIV infection itself and certain ART drugs (didanosine, stavudine, zalcitabine) are likely responsible Manifests with sensory symptoms involving the lower extremities Diagnosis is made clinically after excluding other common causes Management consists of discontinuation of offending drug(s) and control of HIV infection If necessary, analgesics and anticonvulsants can be used for chronic pain Bone disorders Osteopenia, osteoporosis, osteonecrosis, and avascular necrosis of hips have been described Osteopenia is generally asymptomatic, while osteoporosis may present with fractures of the vertebrae, forearms, or hips Interference of vitamin D metabolism by protease inhibitors and lactic acidosis related to NRTI therapy may be responsible for bone loss HIV infection itself may also be a contributing factor Immobility, cigarette smoking, excessive alcohol use, chronic renal failure, hyperthyroidism, and long-term corticosteroid use accentuate bone loss Patients on ART with other risk factors for premature bone loss (eg, postmenopausal women < 65 and all women > 65 years) should consider bone densitometry Calcium and vitamin D should be prescribed in high-risk patients; regular exercise and smoking cessation should be advised Case reports/series of bisphosphonates for treatment NRTI = nucleoside reverse transcriptase inhibitors. smoked a half-pack of cigarettes per day for 15 years. He consumes alcohol approximately twice per week in moderate amounts. Physical Examination Physical examination reveals a blood pressure of 132/ 94 mm Hg, facial wasting (Figure), thinned extremities, and prominent superficial veins. Laboratory studies are noteworthy for a triglyceride level of 880 mg/dl. What are the clinical manifestations of lipodystrophy syndrome? Lipodystrophy syndrome (LDS) refers to a constellation of morphologic and metabolic derangements that include (1) body fat redistribution, (2) dyslipidemia, and (3) glucose intolerance and diabetes mellitus. These abnormalities can occur separately or in combination. Body Fat Redistribution Body fat redistribution is characterized by lipohypertrophy (fat accumulation) and/or lipoatrophy (fat wasting). Physical findings of lipohypertrophy may include a prominent dorsocervical fat pad ( buffalo hump ), breast enlargement, abdominal visceral fat deposition, and lipomatosis (localized areas of fat accumulation). In lipoatrophy, the main physical findings include sunken cheeks and thinning of the buttocks and extremities associated with prominent veins (pseudovenomegaly) related to the loss of subcutaneous fat. Lipohypertrophy and lipoatrophy can occur separately or together, and they may involve 1 or multiple body regions. Dyslipidemia LDS-associated lipid abnormalities include increased serum total cholesterol, triglyceride, and LDL levels and decreased high-density lipoprotein (HDL) levels, although increases in HDL have been reported with non-nucleoside reverse transcriptase inhibitors (NNRTIs) [1 3]. These various lipid www.turner-white.com Vol. 13, No. 6 June 2006 JCOM 343

treatment complications in HIV Figure. Facial wasting. (Reprinted with permission from Carr A. Cooper DA. Images in clinical medicine. Lipodystropy associated with an HIV-protease inhibitor. N Engl J Med 1998;339: 1296. Copyright 1998, Massachusetts Medical Society. All rights reserved.) abnormalities, like the manifestations of body fat redistribution, may occur separately or together. Individuals who have genetic susceptibility for dyslipidemia may be more likely to develop lipid abnormalities in the context of ART. Glucose Intolerance and Diabetes Mellitus While many patients on ART have a normal fasting serum glucose levels, mild subclinical glucose intolerance is common. Less frequent manifestations include abnormal fasting glucose levels and diabetes mellitus. Glucose intolerance and insulin resistance are sometimes observed in HIV-infected persons with significant body fat redistribution, although they may also occur independently. It is not known what proportion of patients with insulin resistance will ultimately develop diabetes mellitus, although obesity and a family history clearly predispose to this complication. What is known about the epidemiology and pathogenesis of LDS? Each component of LDS is thought to be associated with long-term ART exposure. However, the relative contribution of the different ART drug classes appears to vary. Since many of these complications manifest over the course of months and years, information regarding newer medications is incomplete. The pathogenesis of LDS is likely related to a complex interplay of drug, host, and disease factors. Body Fat Redistribution The prevalence of body fat distribution abnormalities in HIV-infected persons on ART ranges between 40% and 50% based on data from large patient surveys [4]. However, there is great variability in prevalence rates between studies, and this is probably related to differences in their case definitions. Initial studies reported the association of fat redistribution with protease inhibitor (PI) therapy [5]. However, more recently, there is an accumulating literature noting the presence of body morphology changes in PI-naive patients. There is a relatively strong correlation between lipoatrophy and nucleoside reverse transcriptase (NRTI) therapy, especially the drugs zidovudine (ZDV) and d4t [6]. The NNRTI class has not been associated with body fat redistribution. Aside from exposure to ART, there are numerous host factors that have been associated with the development of body morphology changes. Among these are white race, older age, longer duration of HIV infection, and greater baseline body mass index. Other factors affecting the development of body fat redistribution include the effectiveness of virologic suppression, baseline state of immunologic function, and degree of immune reconstitution on ART. Gender differences in the clinical manifestations of fat redistribution have been described. Women tend to develop lipohypertrophy while men more frequently manifest lipoatrophy. The extent to which these sex-related differences are related to underlying variations in baseline body habitus is unknown. While there are several hypothesized mechanisms by which the different ART drug classes may lead to body morphology changes, their pathogenesis remains obscure. The inhibition of DNA-polymerase by NRTIs, which is necessary for oxidative metabolism, may be a contributing factor. Dyslipidemia The PI class of ART has been most convincingly associated with hypertriglyceridemia and hypercholesterolemia. There are variations in the degree of dyslipidemia seen with specific PIs. For example, indinavir has relatively lesser effect on lipid levels [7], while ritonavir often has a greater effect [8]. Atazanavir, one of the newer PIs, has not been associated with dyslipidemia [9]. The NNRTI drug class also appears to alter the lipid profile, although the evidence is less well established than for PIs. Nevirapine is thought to cause increased LDL and HDL levels [1], and decreased triglyceride levels have been noted in hypertriglyceridemic patients who have been switched from a PI to an NNRTI [10]. There are conflicting studies with respect to the effect of efavirenz on the lipid profile. There is less compelling evidence linking the NRTI drug class to dyslipidemia. However, since NRTIs are frequently a component of ART regimens, it may be that they potentiate or augment the effects of PIs and NNRTIs on lipid dysregulation. Genetic predisposition to dyslipidemia also likely affects the susceptibility to ART-associated derangements in lipid 344 JCOM June 2006 Vol. 13, No. 6 www.turner-white.com

case-based review metabolism. Several groups of investigators have reported that HIV-infected subjects with the apolipoprotein E-2 genotype may develop more profound lipid profile abnormalities on PI therapy [11,12]. Glucose Intolerance and Diabetes Mellitus As with dyslipidemia, the PI drug class has been most convincingly associated with glucose intolerance and diabetes mellitus. More than one third of HIV-infected patients on a PI-containing ART regimen will have impaired glucose tolerance, which is most likely related to decreased insulin sensitivity. Diabetes mellitus is considerably less common. However, among the PIs, there do appear to be differences with respect to the risk of developing insulin resistance. Specifically, atazanavir is less likely to induce this abnormality [9]. There is scant literature implicating NNRTIs as a cause of this syndrome. However, several investigators have noted an association between NRTI therapy and increased lipolysis, which may lead to insulin resistance. As with PIs, there is a differential risk among the individual NRTIs of developing glucose intolerance and insulin resistance, with d4t associated with this metabolic syndrome [13]. Lopinavir/ritonavir has also been linked to many of these derangements [13]. While it is not known what proportion of HIV-infected patients will ultimately develop glucose intolerance, those with traditional insulin resistance risk factors, such as sedentary lifestyle, obesity, and family history, appear particularly susceptible to progression to diabetes mellitus in the setting of PI exposure. The precise mechanism by which insulin resistance develops in HIV-infected persons on ART has not been determined. However, there is accumulating evidence suggesting a direct effect of ART, especially PIs, leading to impairment of glucose uptake. Indirectly, ART can lead to body fat redistribution with the development of central obesity and peripheral lipoatrophy, both of which are strongly associated with insulin resistance. What factors account for this patient s manifestations? The patient has lipoatrophy without lipohypertrophy, manifesting as a sunken cheek appearance and thin extremities with prominent veins. Exposure to NRTIs, particularly d4t, is likely responsible for his lipoatrophy. Our patient had pre-existing dyslipidemia, with increased total cholesterol, LDL cholesterol, and triglyceride levels. These abnormalities may have been related to lifestyle issues, such as diet and exercise, and/or represent a genetic predisposition. After starting ART, his triglyceride level became very high, suggesting that the PI nelfinavir magnified his underlying dyslipidemia. Although we do not see clinical evidence of glucose intolerance in our patient at this time, given the underlying association between lipoatrophy and insulin resistance, it may be occult. This concern is heightened by the fact that the patient is taking a PI (nelfinavir); his NRTIs (d4t, 3TC) may also contribute to the development of insulin resistance. How should body fat redistribution in LDS be managed? There is no consensus as to the optimal management of body fat redistribution. Often, the decision is guided by patient preference and prompted by significant discomfort or disfigurement. Several studies have been unable to demonstrate measurable reversal of lipohypertrophy (central obesity) when PI therapy has been discontinued or another drug has been substituted [10,14,15]. However, in persons experiencing lipoatrophy, several studies suggest modest levels of measurable increase in fat when another NRTI (eg, abacavir [ABC], tenofovir [TDF]) is substituted for d4t [16 18]. Nonpharmacologic Interventions There are several nonpharmacologic interventions that have been proposed for managing body fat redistribution. Exercise, including aerobic and resistance activities, may help control and possibly reduce fat accumulation as well increase lean body mass. There is no evidence to support any specialized diet for the management of body fat redistribution in the absence of demonstrated metabolic abnormalities. However, a well-balanced diet that is low in fat appears sensible. Liposuction has been used successfully in the management of lipohypertrophy (buffalo hump, central obesity), and injection therapy with polylactic acid and other compounds has been used in the management of lipoatrophy (facial wasting). However, these interventions do not change the underlying pathophysiology of body fat redistribution and should be considered temporizing measures. Pharmacologic Interventions None of the potential pharmacologic interventions for the management of body fat redistribution can be advised without reservation because there are too few studies showing conclusive benefits. Hormone Therapy Growth hormone and testosterone replacement therapy have a physiologic basis for use in the management of body fat redistribution, although further evaluation is required before they can be recommended. Growth hormone levels may be reduced in HIV-infected persons with central obesity, and www.turner-white.com Vol. 13, No. 6 June 2006 JCOM 345

treatment complications in HIV decreased testosterone levels are sometimes found in HIVinfected men. A recent prospective randomized double-blind, placebo-controlled trial evaluated the effect of testosterone replacement on abdominal obesity [19]. The investigators found that testosterone therapy, administered as 10 g gel, in HIV-positive men with low testosterone levels and abdominal obesity was associated with decreased whole body and abdominal subcutaneous fat content and increased lean body mass [19]. However, further studies will be necessary to validate the safety, efficacy, and appropriate doses of both potential hormone replacement therapies. Insulin-Sensitizing Agents Two insulin-sensitizing agents, the thiazolidinediones and metformin, have been studied as potential pharmacologic interventions for body fat redistribution. Thiazolidinediones increase adipogenesis, so their potential in helping to reverse lipoatrophy is promising. However, several preliminary studies evaluating troglitazone have yielded conflicting results, and this drug was recently removed from the U.S. market because of reports of hepatic toxicity. More recently, a randomized, double-blind, controlled clinical trial evaluating rosiglitazone in HIV-infected persons with hyperinsulinemia and lipoatrophy found improved measurable fat deposition during 3 months of ART [20]. However, because of the small sample size and short follow-up interval of the study, it cannot serve as a definitive endorsement, particularly since a larger 48-week study demonstrated that rosiglitazone had no effect on improving lipoatrophy [21]. A recent randomized, double-blind, placebo-controlled trial evaluated pioglitazone, another thiazolidinedione agent, and results showed some measurable improvement in limb lipoatrophy at 48 weeks in patients on ART that did not contain d4t [22]. Further studies will be required, however, to evaluate the safety of this potential agent relative to its efficacy, as more than 15% of the patients receiving pioglitazone experienced serious adverse events. Metformin has been evaluated as a potential treatment for central obesity. Several studies have shown promising results. For HIV-infected persons with central fat accumulation who also require management of glucose intolerance or diabetes mellitus, metformin may be a reasonable option [23]. However, more recent studies have yielded less encouraging results, with 1 study showing neither rosiglitazone alone, metformin alone, nor the combination of the 2, affecting any significant change on abdominal visceral or subcutaneous adipose tissue over 16 weeks [24]. How should lipid and glucose abnormalities in LDS be managed? Lipid Abnormalities Definitive clinical trials to determine the optimal management of lipid abnormalities in HIV-infected patients on ART have not been performed. However, some recommendations can be made based on smaller pilot studies, observational data, and extrapolation from studies on HIV-negative persons. As in seronegative persons, the initial approach in managing lipid abnormalities in HIV-infected patients without coronary artery disease or diabetes mellitus should be with nonpharmacologic interventions. Adherence to the National Cholesterol Education Program (NCEP) dietary guidelines should be advised. These include (1) dietary restriction of total fat to 25% to 35% of total caloric intake, saturated fat to < 7% of total calories/day, and cholesterol of < 200 mg/day; (2) increased intake of fiber (10 25 g/day); and (3) active attempts at weight reduction and increased physical activity. Reduction of alcohol use should be recommended in persons with very high triglyceride levels [25]. Several studies have shown correction of dyslipidemia when ART is modified to a PI-sparing regimen [5,6]. Changing ART may be particularly useful in HIV-infected persons who have significant pre-existing cardiac risk factors and in those with a family history of lipid abnormalities. However, if ART options are limited because of prior drug toxicity or viral resistance, it is prudent to select the optimal regimen for treating HIV infection regardless of its effect on the lipid profile. Pharmacologic management of dyslipidemia is determined by the nature of the abnormality. Hypertriglyceridemia in HIV-infected patients is generally managed with a fibric acid derivative such as gemfibrozil or fenofibrate. Fish oil therapy may also be useful in this setting. Fasting triglyceride levels of greater than 500 mg/dl should prompt therapeutic intervention. Increased total and LDL cholesterol levels are typically managed with HMG-CoA reductase inhibitors (statins). Pravastatin or atorvastatin is preferred for use in HIV-infected patients on ART to minimize drug-drug interactions. Lovastatin and simvastatin should not be coadministered with PIs. Statins should be started at a low dose in this setting and gradually increased as necessary based on treatment response and drug toxicity. Although both fibric acid derivatives and statins effectively lower lipid levels, triglyceride and cholesterol levels may not completely normalize in HIV-infected patients on ART. Any decision to combine these 2 classes of lipid-lowering agents should be done cautiously, as they have some overlapping toxicities to which HIV-infected persons may be particularly susceptible. Glucose Abnormalities Definitive clinical trials to determine the optimal management of glucose intolerance and diabetes mellitus in HIV-infected patients on ART have not been performed. However, some recommendations can be extrapolated from 346 JCOM June 2006 Vol. 13, No. 6 www.turner-white.com

case-based review studies in HIV-negative persons. In HIV-infected patients with a personal history of glucose intolerance or diabetes mellitus or first-degree relatives with diabetes mellitus, avoidance of PIs in constructing an ART regimen may be helpful [10,15], or, if opting to use a PI, atazanavir should be considered because of its lack of effect on fasting glucose and insulin levels [9]. Diet, exercise, and weight reduction should also be recommended. If treatment of hyperglycemia is necessary, an insulin-sensitizing drug, either metformin or a thiazolidinedione, should be considered. Studies in HIV-infected persons with glucose intolerance and insulin resistance treated with metformin showed increased insulin sensitivity, as well as decreased levels of cardiovascular risk markers [23, 26]. Similarly, early studies in HIV-infected persons with LDS who were treated with troglitazone showed increased insulin sensitivity [27]. A more recent study, with rosiglitazone, showed similar results [28]. If oral medications are inadequate, insulin therapy may be necessary. HIV-infected patients for whom pharmacologic therapy for hyperglycemia is initiated need to be monitored closely for adverse effects. Thiazolidinediones can cause hepatic toxicity and should be avoided in persons with underlying liver disease. Rosiglitazone has been associated with increased total cholesterol, LDL cholesterol, and triglyceride levels in several studies, so it should be used with caution in patients with baseline dyslipidemia [20,21]. Metformin can produce lactic acidemia and should be avoided in those with renal insufficiency. Hepatic and renal function tests should be performed regularly in HIV-infected patients, and lactate levels should be obtained in those with suspected lactic acidemia. How should patients with this syndrome be assessed and monitored? Although there are several different methods to assess body fat distribution, none has been demonstrated to have adequate predictive value to support their use in screening HIV-infected patients. However, some of these methods are relatively inexpensive and easy to perform. Anthropometric measurement of the waist-to-hip ratio is a convenient but nonspecific way to estimate visceral and subcutaneous fat distribution. Waist circumference and sagittal diameter appear to be more sensitive and specific than the waist-to-hip ratio. Some level of training is required in order to yield reproducible anthropometric measurements. Cross-sectional computed tomography or magnetic resonance imaging (MRI) is considered the gold standard for assessing body fat distribution, but their expense and more limited availability preclude a screening role for these studies. Furthermore, there are technical limitations in their ability to image visceral and subcutaneous tissues. Other methods to assess body fat distribution include bioelectrical impedance analysis, dual-energy x-ray absorptiometry (DEXA) scan, and ultrasound, all of which have significant limitations. Bioelectrical impedance analysis for estimating regional body composition as opposed to the whole body, as required for determining visceral and subcutaneous fat distribution, has not been validated. DEXA scan is useful for determining appendicular fat but is less suitable for estimating visceral adipose tissue. Ultrasound may be better than DEXA scan for measuring specific adipose tissue compartments and for allowing more accurate distinction between adipose and nonadipose body compartments, but there is limited experience with this modality in HIVinfected persons. Since many of these radiologic methods for determining body fat distribution are costly, have technical limitations, and/or have not been standardized for HIV infection, it seems reasonable to screen patients with anthropometric measurements. Certain measurements have been demonstrated to correlate with health outcomes (waist-to-hip ratio) or have been incorporated into cardiovascular risk assessments in NCEP guidelines (waist circumference). Serial photographs of the affected parts of the patient s body may be useful adjunctively. A reasonable approach in the case patient would be to follow anthropometric measurements and facial photographs over time. Before initiating ART in HIV-infected patients, a fasting lipid profile, including total, LDL, and HDL cholesterol levels and a triglyceride level, should be performed. These laboratory studies should also be done prior to and after an ART regimen is modified. Monitoring should continue in all patients every 6 to 12 months thereafter. Since ART, especially PIs, may exacerbate underlying glucose intolerance, it is prudent to obtain a fasting glucose prior to initiating ART. Thereafter, monitoring every 3 to 6 months is recommended. Administration of an oral glucose tolerance test to an HIV-infected patient may help delineate subsequent risk for diabetes mellitus or body fat redistribution, but it is not recommended for screening. What would be the appropriate management of this patient? As the patient has facial wasting but no fat accumulation, the most appropriate course of action would be to substitute another NRTI, preferably ABC or TDF, for d4t. Because of the concern about his appearance, he could also be referred for injection therapy. www.turner-white.com Vol. 13, No. 6 June 2006 JCOM 347

treatment complications in HIV He also had increased total and LDL cholesterol levels and hypertriglyceridemia at baseline. However, with exposure to ART, his triglyceride level became markedly higher, which places him at risk for developing pancreatitis. Nonpharmacologic measures, such as diet, exercise, weight reduction (if necessary), and cessation of cigarette smoking and alcohol use, should be recommended. In addition, our patient may benefit from switching his ART to a PI-sparing regimen or by switching nelfinavir to atazanavir, a PI that will not adversely affect his lipid profile. If there is no improvement of his hypertriglyceridemia with nonpharmacologic interventions, fibric acid derivative or fish oil therapy should be initiated. Is LDS associated with an increased risk of atherosclerotic disease? The evolving literature, while not definitive, suggests that HIV-infected patients on ART may be at some increased risk for atherosclerotic disease. Several studies have shown an increased carotid intima-media thickness (IMT), a surrogate marker of atherosclerosis, in HIV-infected individuals with LDS and antiretroviral exposure [29 31]. However, other studies have also found no significant effect of either lipodystrophy or ART on carotid IMT beyond the attributable risks due to conventional cardiac risk factors [32]. Still other investigations found no association between HIV infection or PI exposure and significant progression of carotid IMT [33]. This lack of association was observed to 3 years of follow-up [34]. Based on the currently available evidence, which is not able to demonstrate incontrovertible support for an association between LDS and increased risk of atherosclerosis, it is reasonable to conclude that the benefits of ART, if prescribed according to current guidelines, would still likely outweigh the potential risks. However, the presence of cardiovascular risk factors should be considered in selecting which antiretroviral regimen to use. There is scant literature addressing the risk of HIVinfected persons with body fat redistribution developing atherosclerotic disease in the absence of metabolic abnormalities. However, in such individuals, there may be occult glucose intolerance without fasting hyperglycemia. One recent prospective observational study found that ART was associated with a significant (26%) relative increase in the rate of myocardial infarction per year of exposure during the first 4 to 6 years of use [35]. The study investigators defined the variable of lipodystrophy as body fat redistribution and made a separate distinction for hypercholesterolemia, hypertriglyceridemia, and diabetes mellitus. In their analysis, there was no significant association of lipodystrophy with risk of myocardial infarction. The majority of recent studies addressing risk of cardiac disease in HIV-infected persons were evaluating the possible association of ART with atherosclerotic disease and not specifically the effect of LDS. However, it is reasonable to assume that hypercholesterolemia, which has been shown to be a risk factor for atherosclerotic disease in the general population, is also one in HIV-infected persons. A recent prospective observational study evaluated particular variables on the risk of myocardial infarction and it showed a small, but statistically significant, increased relative rate of myocardial infarction in HIV-infected persons on ART with hypercholesterolemia or hypertriglyceridemia [35]. Further investigations of this cohort revealed that an increased risk of PI exposure was associated with an increased risk of myocardial infarction, partly attributable to dyslipidemia; however a similar associated risk of myocardial infarction was not seen with NNRTI exposure [36]. It is reasonable to assume that diabetes mellitus, which has been shown to be a risk factor for atherosclerotic disease in the general population, is also one in HIV-infected persons. In the above-mentioned prospective observational study, there was a statistically significant increased relative rate of myocardial infarction in HIV-infected persons on ART with diabetes mellitus [35]. This increased rate was greater than that seen with either hypercholesterolemia or hypertriglyceridemia. The study investigators did not address whether there was an increased risk of myocardial infarction in persons with glucose intolerance. Case Study 2 Initial Presentation A 28-year-old woman who was diagnosed with HIV infection 3 years ago presents with the complaints of fatigue and occasional diarrhea. History At the time of diagnosis, she presented with recurrent vulvovaginal candidiasis. Her baseline CD4 cell count was 220/mm 3 and her viral load was more than 100,000 copies/ ml. She was started on d4t, 3TC, and lopinavir/ritonavir. Her CD4 cell count has increased to 660/mm 3 and her viral load has been less than 50 copies/ml. The fatigue and diarrhea have developed over the past few months. Physical Examination Physical examination is normal. Laboratory studies show a normal complete blood count and renal and hepatic function tests, and stool is negative for pathogens. Her venous lactate level is 3.8 mmol/l, and her arterial ph is 7.36. 348 JCOM June 2006 Vol. 13, No. 6 www.turner-white.com

case-based review What are the clinical manifestations of lactic acidemia/ acidosis? Lactic acidemia is defined as an increased venous lactate level (> 18 mg/dl or > 2 mmol/l) in the context of a normal arterial ph. It may be asymptomatic or associated with a variety of nonspecific symptoms, signs, and laboratory abnormalities. Symptoms may include fatigue, weight loss, nausea, vomiting, abdominal pain, dyspnea, and palpitations. Physical examination is generally normal but may show hepatomegaly or peripheral edema. Stigmata of chronic hepatic disease, indicating the presence of steatosis, are seen less often. Laboratory studies may show increased transaminase levels. Lactic acidosis is characterized by the presence of an increased venous lactate level and a low arterial ph (< 7.35). Symptoms are usually present in the context of lactic acidosis. What is known about the epidemiology and pathogenesis of lactic acidosis/acidemia? Asymptomatic lactic acidemia has been reported in up to 20% of patients receiving at least 1 NRTI compared with less than 1% of those not on ART [6,37 39]. Specific host factors, such as ethnicity, gender, or age, have not been shown to predict the development of lactic acidemia. Symptomatic lactic acidemia and lactic acidosis are less common than the asymptomatic form, affecting 1.5% to 2.5% of patients on NRTIs, with an estimated incidence of 0.4 to 0.8 per 100 patient-years of observation [38]. Fatal cases of lactic acidosis have been described in HIV-infected pregnant women receiving d4t and/or didanosine (ddi), and these drugs are no longer recommended in this setting [40]. The NRTIs predispose to lactic acidemia by interfering with the function of mitochondrial DNA-polymerase, which is necessary for aerobic metabolism, resulting in multiple organ dysfunction. Lactic acidemia has been associated with hepatic steatosis, lipoatrophy, peripheral neuropathy, and osteopenia. What factors are associated with this patient s symptoms? The case patient would be characterized as having symptomatic lactic acidemia, although her diarrhea could also represent a side effect of lopinavir/ritonavir. The symptomatic lactic acidemia is mostly likely attributable to NRTI exposure (d4t, 3TC). She does not appear to have any specific organ dysfunction. How should this patient s condition be managed? Recommendations for management of NRTI-associated lactic acidemia arise from extrapolation from clinical observations and consensus guidelines. There are no clinical trials addressing this issue in HIV-infected persons. A venous lactate level of greater than 5 mmol/l in association with the described symptoms or a venous lactate level greater than 10 mmol/l regardless of symptoms establishes the diagnosis of lactic acidemia [41]. In such patients, if no other cause is identified, the suspected responsible ART drugs should be discontinued. Following resolution of lactic acidemia, a modified ART regimen can be restarted. In patients who are symptomatic but have venous lactate levels less than 5 mmol/l, NRTIs may be continued, if necessary, with careful monitoring of lactate levels over time. Several agents, including thiamine, riboflavin, antioxidants (vitamins C, E, and K), coenzyme Q, and L- carnitine, have been used in the management of lactic acidemia in the setting of congenital mitochondrial disease. However, only anecdotal reports support their use in treating NRTI-associated lactic acidemia. Based on published reports, mild to moderate lactic acidemia resolves within weeks to months after discontinuation of the responsible NRTIs [26]. Patients with lactic acidosis face a much worse prognosis, with a mortality rate as high as 80%. At this time, it is not known whether there are any chronic sequelae of mild to moderate lactic acidemia. Our patient s moderate lactic acidemia (3.8 mmol/l) would permit continued monitoring on her current ART regimen in the absence of symptoms. However, in that she has fatigue and occasional diarrhea, modification of her ART should be considered. One option would be to substitute TDF, which is not highly associated with lactic acidemia, for d4t. Should HIV-infected patients be screened for lactic acidosis/acidemia? Because it is impossible to predict who will develop lactic acidemia, screening HIV-infected patients on NRTIs with venous lactate levels is not recommended. However, patients who have symptoms or signs that are suggestive of lactic acidemia should have a venous lactate level checked and, if high, repeated to confirm the diagnosis. Laboratory www.turner-white.com Vol. 13, No. 6 June 2006 JCOM 349

treatment complications in HIV abnormalities that should trigger evaluation for lactic acidemia include unexplained increased transaminase levels, an increased anion gap, low bicarbonate or chloride levels, and hypoalbuminemia. Falsely increased venous lactate levels are frequent but can be minimized by ensuring appropriate specimen collection on ice and rapid processing. Patients should be adequately hydrated and avoid strenuous exercise for at least 1 day prior to specimen collection if possible. An abnormal venous lactate level should be repeated for confirmation before diagnosing lactic acidemia. Case Study 3 Initial Presentation A 44-year-old man who was diagnosed with HIV infection in 1992 presents with Pneumocystis jiroveci (formerly carinii) pneumonia. History At baseline, his CD4 cell count was 88/mm 3. He was initially treated with ZDV and 3TC, but his regimen was changed to d4t, 3TC, and indinavir in 1997. More recently, he has been on ddi, TDF, and efavirenz. His most recent CD4 cell count was 420/mm 3, and his viral load was less than 50 copies/ ml. Over the past year, he has complained of an increasing pins and needles sensation in his feet without other neurologic symptoms. Physical Examination Physical examination shows absent ankle jerks and decreased sensation to pin prick and light touch in a stocking distribution to the mid-shins. Laboratory studies are noteworthy for normal thyroid-stimulating hormone and folate and vitamin B 12 levels and a nonreactive rapid plasma reagin test. What are the clinical manifestations of peripheral neuropathy? Peripheral neuropathy in HIV-infected patients may represent toxicity related to ART or a complication of HIV infection itself. The most common neuropathic syndrome associated with ART is a distal symmetric sensory polyneuropathy. This type of peripheral neuropathy manifests as a tingling and numbness, predominantly in the lower extremities, often beginning in the toes and gradually extending proximally over time. Neurologic examination reveals a stocking-glove type sensory loss involving all modalities. There may also be reduced or absent deep tendon reflexes at the ankles and, in more severe cases, at the knees. Strength testing of the lower extremities is usually normal. Diagnosis of peripheral neuropathy is generally made on the basis of clinical evaluation. Electromyography/nerve conduction studies, which would show a predominantly axonal sensorimotor polyneuropathy, are rarely necessary. Laboratory studies, including glucose, renal and hepatic function tests, thyroid-stimulating hormone, folate and vitamin B 12 levels, and rapid plasma reagin test, should be performed to rule out other possible etiologies. What is known about the epidemiology and pathogenesis of drug-induced peripheral neuropathy? The pathogenetic mechanisms by which distal symmetric sensory polyneuropathy arises in HIV disease remain poorly defined. However, it is thought to be multifactorial in etiology. HIV has been cultured from peripheral nerve in some patients, suggesting a direct role for the virus in its pathogenesis [42 44]. There is also evidence to suggest that an immunologically mediated inflammatory process may contribute to the development of symptoms [45 47]. Druginduced peripheral neuropathy may occur at any stage of HIV disease. Compared with HIV-related peripheral neuropathy, it may be more likely to involve the hands, have a more abrupt onset, progress more rapidly, and be more painful [48 51]. Drug-induced peripheral neuropathy is associated with NRTI use, in particular, ddi, d4t, and zalcitabine (ddc). While the precise mechanism of drug-induced peripheral neuropathy remains unknown, there is evidence to suggest mitochondrial toxicity as a contributing factor. ZDV and the remaining NRTIs are not thought to be neurotoxic. The incidence of drug-induced peripheral neuropathy is dosedependent and also increases with the duration of exposure to the offending agent. The onset of symptoms typically occurs a few months after initiation of therapy. What factors are associated with this patient s symptoms? The patient s symptoms fit the syndrome of distal symmetric sensory polyneuropathy. He is experiencing paresthesias of both feet and has evidence of sensory loss and absent deep tendon reflexes. The time course of symptom progression (over 1 year) is also consistent with this syndrome. His laboratory test results exclude other potential causes of peripheral neuropathy. His previous exposure to d4t and current use of ddi are most responsible for the development of his peripheral neuropathy. However, HIV infection itself could also be a contributing factor. 350 JCOM June 2006 Vol. 13, No. 6 www.turner-white.com

case-based review How should this patient s peripheral neuropathy be managed? Unfortunately, management options for drug-induced peripheral neuropathy are limited. Cessation of the neurotoxic medication is usually beneficial, but improvement may take weeks to months. Treatment is aimed at symptom control, particularly minimizing the severity of dysesthesias. Nonsteroidal anti-inflammatory drugs, tramadol, narcotics, and transdermal lidocaine have been used with varying degrees of success. Anticonvulsants (gabapentin, carbamazepine, phenytoin, topiramate, lamotrigine) have also been effective in some patients. Of these, only lamotrigine has been studied in HIV-infected patients. In a small randomized, placebo-controlled trial [52], improved pain scores were seen in comparison with placebo, but the lamotrigine group had a higher dropout rate from side effects (predominantly rash). Other management options, including amitriptyline, mexilitene, topical capsaicin, and acupuncture, for peripheral neuropathy have not been shown to be superior to placebo in double-blind trials. Recent studies have also failed to show efficacy of recombinant human nerve growth factor or vibratory stimuli [53,54]. A small uncontrolled trial investigating the use of L-acetyl-carnitine for the management of drug-induced neuropathy showed some beneficial effect [55]. A small, short-term study suggested that a solution of topical aspirin in diethyl ether may also lead to symptomatic improvement [56]. What is the appropriate care of this patient? The ddi should be stopped and replaced with another NRTI (perhaps abacavir [ABC]). If cessation of ddi does not lead to symptomatic improvement over time, any of the described therapeutic interventions may be attempted. The choice of which drug(s) to use is based on the severity of the pain, the drug side effect profile, and the avoidance of significant drug-drug interactions. Case Study 4 Initial Presentation A 52-year-old man who was diagnosed with HIV infection in 1988 presents with progressive left hip pain with walking. History The patient has had several opportunistic diseases, including P. jiroveci pneumonia, cryptococcal meningitis, and Kaposi s sarcoma. His baseline CD4 cell count was 26/mm 3. He has been on numerous ART regimens and is currently taking ABC, TDF/emtricitabine, lopinavir/ritonavir, fosamprenavir, and enfuvirtide. His most recent CD4 cell count was 348/mm 3, and his viral load was 1200 copies/ml. Over the past few months, he has complained of left hip pain that is worse with walking. Physical Examination Physical examination shows decreased range of motion secondary to pain but no other abnormalities. His hip radiographs are normal, but MRI shows evidence of left hip avascular necrosis. What are the clinical manifestations of bone disorders associated with ART? The bone abnormalities associated with ART include (1) osteopenia (mild to moderate bone loss), (2) osteoporosis (severe bone loss), (3) osteonecrosis (bone tissue death due to circulatory insufficiency), and (4) avascular necrosis of the hips. Osteonecrosis has been most often reported to involve the femoral and humeral heads, proximal tibia, femoral condyles, and hand and wrist bones. While bone abnormalities were described in HIV-infected persons before the advent of highly active ART [57 59], such complications are being observed with greater frequency in recent years [60 62]. Osteopenia and osteoporosis are diagnosed by bone densitometry using DEXA scanning. Osteopenia is defined as between 1 and 2.5 standard deviations below the mean value of a sex-matched control, and osteoporosis is defined as more than 2.5 standard deviations below this value. Osteopenia is asymptomatic, but osteoporosis may present as fractures of the hips, vertebrae, or forearms. Osteonecrosis may be asymptomatic or present as pain involving a bone or joint. Avascular necrosis of the hips may also be asymptomatic or present as pain with ambulation. MRI is necessary to diagnose osteonecrosis and avascular necrosis of the hips because standard radiographs are not highly sensitive for these conditions. What is known about their epidemiology and pathogenesis? In HIV-negative persons, factors associated with accelerated bone loss include immobility, excessive alcohol consumption, severe weight loss, hyperthyroidism, hypogonadism, parathyroid disease, cigarette smoking, and chronic corticosteroid exposure. Precipitating factors for osteonecrosis www.turner-white.com Vol. 13, No. 6 June 2006 JCOM 351

treatment complications in HIV in HIV-negative persons include alcohol abuse, hemoglobinopathies (eg, sickle cell disease), corticosteroid exposure, hyperlipidemia, hypercoagulability, and systemic lupus erythematosus [60,63,64]. Studies in HIV-infected patients on ART have reported rates of osteopenia of 22% to 50% and rates of osteoporosis of 3% to 21% [62,65,66]. Both NRTIs and PIs have been associated with osteopenia in this population [62,66,67]. It is believed that HIV infection itself, especially advanced disease, may also play a role [68]. Several mechanisms by which ART may predispose to osteopenia have been proposed. PI use has been associated with increased levels of osteocalcin [67], which is responsible for increased bone turnover. Disruption of vitamin D metabolism has also been suggested as a mechanism of PI-induced osteopenia. NRTIrelated lactic acidemia has been implicated as a contributing factor to bone loss as well [65]. Several recent studies have linked hyperlipidemia and corticosteroid use with osteonecrosis [60,63,64]. The predisposing factors and prevalence of avascular necrosis of the hips in HIV-infected persons have not been determined. It is likely that the patient s prior advanced HIV disease and his NRTI and PI exposures have contributed to its development. How should they be managed? Patients with HIV infection on ART who are diagnosed with osteopenia or osteoporosis should be counseled regarding modifiable risk factors, such as immobility, cigarette smoking, alcohol consumption, and chronic corticosteroid use, all of which are known to accelerate bone loss. Additionally, they should be advised to consume foods with adequate calcium and vitamin D, using supplements if dietary intake is insufficient. Regular exercise and weight-bearing activity are additional measures that should be recommended. There is inadequate evidence to support the use of bisphosphonates or androgen therapy for HIV-infected persons with osteopenia, although therapeutic intervention is advised in those with osteoporosis, especially if there is a history of fracture. For patients experiencing symptomatic osteonecrosis or avascular necrosis of the hips, surgical resection and joint replacement are recommended if there is significant functional impairment or if pain control cannot be achieved with medical therapy. Should HIV-infected patients be screened for bone disorders? There is no evidence to support the screening of most HIVinfected persons for osteopenia/osteoporosis, osteonecrosis, or avascular necrosis. However, HIV-infected persons on ART who have additional risk factors for premature bone loss may benefit from baseline DEXA scanning. If this test is abnormal, a follow-up study to assess progress should be considered 2 years after the appropriate intervention. Women aged 65 or older and postmenopausal women younger than age 65 who have 1 or more additional risk factors for accelerated bone loss should be monitored with bone densitometry periodically for progression. Corresponding author: Elisa I. Choi, MD, Beth Israel Deaconess Medical Center, Div. of Infectious Diseases, 330 Brookline Ave., Boston, MA 02215, echoi@bidmc.harvard.edu. Financial disclosures: None. Author contributions: conception and design, EIC, HL; analysis and interpretation of data, EIC; drafting of the article, EIC, HL; critical revision of the article, EIC, HL; collection and assembly of data, EIC. References 1. Van Der Valk M, Kastelein JJ, Murphy RL, et al. Nevirapinecontaining antiretroviral therapy in HIV-infected patients results in an anti-atherogenic lipid profile. AIDS 2001;15:2407 14. 2. Friis-Moller N, Weber R, Reiss P, et al. Cardiovascular disease risk factors in HIV patients-association with antiretroviral therapy: results from the DAD study. 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Marked hyperlipidemia on ritonavir therapy. AIDS 1997;11:938 9. 9. Jemsek JG, Arathoon E, Arlotti M, et al. Body fat and other metabolic effects of atazanavir and efavirenz, each administered in combination with zidovudine plus lamivudine, in antiretroviral-naive HIV-infected patients. Clin Infect Dis 2006; 42:273 80. 10. Martinez E, Conget I, Lozano L, et al. Reversion of metabolic abnormalities after switching from HIV-1 protease inhibitors to nevirapine. AIDS 1999;13:805 10. 352 JCOM June 2006 Vol. 13, No. 6 www.turner-white.com